Androgens and bone turnover in men

The opposing activities of osteoblasts forming new bone and osteoclasts resorbing old bone create the continuous process ofbone remodeling. While these actions are antagonistic, both types of cells exert mutual influence ofboth positive and negative nature on each other via paracrine cross-talk to maintain an equilibrium. Quantitative bone histomorphometry of biopsies to assess parameters of this homeostasis are useful in animal studies but are of restricted applicability in patients. In this case, chemical markers of osteoblast- and osteoclast activities, hence bone turnover, can be assessed in blood and urine. Osteoblast activity is reflected by concentrations of type 1 procollagen extension peptides (carboxy-terminal: P1CP or amino-terminal: P1NP) and other non-collagenous proteins secreted by osteoblasts, such as osteocalcin and bone specific alkaline phosphatase (BSAP). Also osteoprotegerin (OPG), as a decoy receptor for RANKL (see 7.2.2) can serve as marker of osteoblast action. Bone resorption, hence osteoclast activity, can be estimated by urinary excretion of degradation products of type I collagen, such as pyridinium crosslinks (deoxypyridinoline, DPD) and collagen type I cross-linked N-telopeptide (NTX) (Riggs etal. 2002).

Small uncontrolled studies in hypogonadal men suggest an elevation of bone turnover: both markers of osteoblastic activity (osteocalcin and BSAP) and osteoclastic action (urinary hydroxyproline excretion) were found to be elevated in such patients (Goldray etal. 1993; Jackson etal. 1987; Stepan etal. 1989). Correspondingly, in healthy younger men, testosterone levels are negatively associated both with serum BSAP and urinary DPD concentrations. As the CAG repeat polymorphism of the androgen receptor gene is involved in this association (longer repeats mitigating androgen effects are positively related to BSAP and DPD levels), effects are most likely directly linked to androgens and their receptor (Zitzmann et al. 2001) (see 3.4.5). It can be speculated that the lower androgen levels allow for higher bone resorption activity. In counter-regulation, bone formation would be upregulated. In case of hypogonadism, this still would result in an dysequilibrium pointing towards bone resorption.

Several studies have addressed the effects of testosterone administration to hypo-gonadal men in regard to markers of bone turnover. In a large, uncontrolled studyin over 200 hypogonadal men receiving testosterone gel for substitution, it was demonstrated bone that osteocalcin and PINP concentrations increased transiently upon elevation of androgen concentrations, returning to baseline after the initial 90 days of treatment, while NTX as bone resorption marker decreased dose-dependently (Wang et al. 2001). This confirms earlier reports (Katznelson et al. 1996; Wang etal. 1996).

While the study involving the androgen receptor polymorphism points to a direct androgen effect, it cannot be concluded from the interventional trials whether the effects of testosterone are caused directly or by its aromatization-metabolite estradiol (also see 7.2.5); this has been adressed by two short-term studies with a sophisticated design. One trial involved 59 healthy men aged 68 ± 6 years whose endogenous sex steroid production was suppressed by a long-acting GnRH agonist and an aromatase inhibitor; subjects were then randomized to four groups receiving transdermal substitution of either testosterone and estradiol, testosterone alone, estradiol alone or placebo. The respective treatment times lasted, however, only three weeks (Falahati-Nini et al. 2000). Another group used a similar approach which lasted 12 weeks: 70 younger healthy men aged 20 to 44 years were treated with a long-acting GnRH agonist and randomized to three groups receiving either no substitution or transdermal testosterone with or without aromatase inhibitor (Leder etal. 2003). Since the first approach is shorter but involves an estrogen-alone group, there is some dispute between the authors which design yields the most useful answers (Khosla and Riggs vs. Leder and Finkelstein 2003). The results are more or less uniform in regard to bone resorption markers: The shorter study sees a marked increase of urinary DPD and NTX excretion in the placebo-treated hypogonadal group in comparison to baseline. Treatment with testosterone alone showed a trend to reduce these effects, while treatment with estradiol alone inhibits bone resorption to a stronger extent, but not fully. In the group receiving both sex steroids, no difference to baseline values was observed (Falahati-Nini et al. 2000). Corresponding results were seen in the longer study involving younger men, although testosterone effects on DPD excretion were significant (Leder et al. 2003). This demonstrates that androgens and estrogens play an independent and fundamental role in inhibition of bone resorption.

In regard to bone formation markers, results differ: the shorter study found that serum osteocalcin and P1NP declined at three weeks of estrogen and testosterone deficiency. Estrogen alone was able to prevent the decrease in both formation markers, whereas testosterone alone (in the presence of an aromatase inhibitor) prevented the decrease in osteocalcin, but not in P1NP. Continued treatment with both sex steroids resulted in no change in the formation markers. It was concluded that both estrogen and testosterone are important in the maintenance of mature osteoblas-tic function. It remains speculative whether differences between both markers are due to the fact that osteocalcin isa relatively late marker in osteoblast differentiation, possibly inhibiting apoptosis, and due to the fact that P1NP is produced throughout osteoblast differentiation (Falahati-Nini etal. 2000). In contrast, in the second, longer study, the untreated hypogonadal men exhibited an increase of the bone formation markers osteocalcin, P1CP and P1NP which was counteracted by testosterone alone and, to a stronger extent, by both sex steroids. It remains unresolved whether these contrasts are due to differences in the study populations (younger vs. older men) or caused by observations at different time-points, suggesting that the shorter study was better able to separate direct effects of gonadal steroid deprivation (such as increased osteoblast apoptosis) from indirect ones (resorption-coupled increase in osteoblast activity) (Khosla and Riggs vs. Leder and Finkelstein 2003). The results of the longer study are in agreement with observations of increased markers of bone formation in clinical long-term hypogonadism. Also weaker androgen effects due to longer CAG repeats in the androgen receptor gene (see above) may reflect both increased bone formation and resorption.

In conclusion, an independent role of androgens in protectingbone mass, both by promotingbone formation and attenuatingbone resorption has been demonstrated in humans. Nevertheless, the role of its metabolite estradiol is pivotal in bone metabolism (see 7.2.5).

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